POSTTRANSCRIPTIONAL REGULATION OF TRANSFORMING GROWTH FACTOR-BETA 1

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In many cell types there is a large discrepancy between the measured levels of transforming growth factor-beta (TGF-beta1) mRNA and protein. This suggests that translational or post-translational mechanisms play an important role in the regulation of TGF-beta1 production. Clinically important members of the steroid hormone superfamily affect both these processes. We have identified a novel upstream start site in the TGF- beta1 MRNA, and have investigated the effects of start site usage on translational regulation of the MRNA by generating constructs in which various portions of the 5' and 3' UTRs have been deleted. From the results of in vitro translation experiments, a gross map of the cis- acting elements that regulate the translational efficiency has been constructed. The 3' UTR consistently stimulates translation, while the 5' UTR contains both stimulatory and inhibitory elements. Selection of alternative transcriptional start sites determines which of these elements dominates, and allows translational efficiency of the TGF-beta1 MRNA to vary over a 16-fold range. Methodology has been developed for accurate measurement of TGF-betas in the plasma of human subjects. The antiestrogen, tamoxifen, which increases TGF-beta1 levels in the tumor stroma of women with breast cancer, has no effect on circulating TGF- beta1 levels. An understanding of the mechanisms whereby steroids and related compounds regulate the production and activity of the TGF-beta family of growth inhibitors may allow the rational design of more potent pharmacological agents for use in chemoprevention or chemotherapy of cancer.